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Abstract Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC8 or ERCC6. Most pathogenic variants in ERCC8 are single nucleotide substitutions. Structural variants (SVs) have been reported in patients with ERCC8-related CS. However, comprehensive molecular detection, including SVs of ERCC8, in CS patients remains problematic. Herein, we present three Japanese patients with ERCC8-related CS in whom causative SVs were identified using whole-exome-based copy number variation (CNV) detection tools. One patient showed compound heterozygosity for a 259-kb deletion and a deletion of exon 4 which has previously been reported as an Asia-specific variant. The other two patients were homozygous for the same exon 4 deletion. The exon 4 deletion was detected only by the ExomeDepth software. Intrigued by the discrepancy in the detection capability of various tools for the SVs, we evaluated the analytic performance of four whole-exome-based CNV detection tools using an exome data set from 337 healthy individuals. A total of 1,278,141 exons were predicted as being affected by the 4 CNV tools. Interestingly 95.1% of these affected exons were detected by one tool alone. Thus, we expect that the use of multiple tools may improve the detection rate of SVs from aligned exome data.

Once fertilized, mouse zygotes rapidly proceed to zygotic genome activation (ZGA), during which long terminal repeats (LTRs) of murine endogenous retroviruses with leucine tRNA primer (MERVL) are activated by a conserved homeodomain-containing transcription factor, DUX. However, Dux-knockout embryos produce fertile mice, suggesting that ZGA is redundantly driven by an unknown factor(s). Here, we present multiple lines of evidence that the multicopy homeobox gene, Obox4, encodes a transcription factor that is highly expressed in mouse two-cell embryos and redundantly drives ZGA. Genome-wide profiling revealed that OBOX4 specifically binds and activates MERVL LTRs as well as a subset of murine endogenous retroviruses with lysine tRNA primer (MERVK) LTRs. Depletion of Obox4 is tolerated by embryogenesis, whereas concomitant Obox4/Dux depletion markedly compromises embryonic development. Our study identified OBOX4 as a transcription factor that provides genetic redundancy to preimplantation development.

Introduction: In this study, we aim to estimate the natural standing sagittal alignment in patients with adult spinal deformity (ASD), firstly by investigating the normative values of anatomical pelvic parameters based on the anterior pelvic plane (APP) in a healthy population, and to clarify the relationships between the anatomical and positional pelvic parameters in standing position. Methods: The images of biplanar slot-scanning full-body stereoradiography in 140 healthy Japanese volunteers (mean age, 39.5 years; 59.3% female) were examined. In addition to three-dimensional measurements including pelvic incidence (PI), sacral slope (SS), and pelvic tilt (PT), the APP angle (APPA; anterior tilting=positive) was measured as the angle between the APP and the vertical line using the two-dimensional lateral image. Anatomical SS and PT (aSS and aPT) were calculated as the angles of SS and PT in reference to APP. Results: The mean (range) values of APPA, aSS, and aPT were determined to be 0.7° (−16.8°/15.5°), 36.8° (18.3°/64.9°), and 13.2° (−0.6°/28.7°), respectively. Moreover, SS was found to be significantly correlated with PI and aSS, while PT was significantly correlated with PI, aSS, aPT, and body weight. Also, PT was significantly larger in females than in males. Multiple linear regression analysis deduced the following equations: SS=0.404×aSS+0.203×PI+12.463, PT=−0.391×aSS+0.774×PI+1.950×sex (male=0, female=1)−12.971, wherein aSS had the greatest effect for predicting SS among the included factors and PI had the greatest effect for predicting PT. In addition, no significant differences were noted between PT/PI and aPT/PI. Conclusions: As per the results of this study, significant correlations were noted among parameters and predicting models for positional parameters (SS and PT) using anatomical parameters (aSS and aPT) in a healthy population. This novel measurement concept based on the APP has been considered to be useful in estimating natural SS and PT in standing position using the anatomical pelvic parameters in patients with ASD.

In the transsylvian (TS) approach, as characterized by clipping surgery, the presurgical visualization of the superficial middle cerebral vein (SMCV) can help change the surgical approach to ensure safe microsurgery. Nevertheless, identifying preoperatively the venous structures that are involved in this approach is difficult. In this study, we investigated the venous structures that are involved in the TS approach using three-dimensional (3D) rotational venography (3D-RV) and evaluated the effectiveness of this method for presurgical simulation. Patients who underwent 3D-RV between August 2018 and June 2020 were involved in this retrospective study. The 3D-RV and partial maximum intensity projection images with a thickness of 5 mm were computationally reconstructed. The venous structures were subdivided into the following three portions according to the anatomic location: superficial, intermediate, and basal portions. In the superficial portion, predominant frontosylvian veins were observed on 31 (41%) sides, predominant temporosylvian veins on seven (9%) sides, and equivalent fronto- and temporosylvian veins on 28 (37%) sides. The veins in the intermediate (deep middle cerebral and uncal veins) and basal portions (frontobasal bridging veins) emptied into the SMCV on 57 (75%) and 34 (45%) sides, respectively. The 3D-RV images were highly representative of the venous structures observed during microsurgery. In this study, 3D-RV was utilized to capture the details of the venous structures from the superficial to the deep portions. Presurgical simulation of the venous structures that are involved in the TS approach using 3D-RV may increase the safety of microsurgical approaches.

Abstract Background Although transbronchial diagnostic procedures are sometimes difficult to perform because of the patient’s respiratory or general conditions, endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA), a known transesophageal diagnostic procedure, might be useful for such cases. We conducted this prospective three-center observational study to evaluate the safety and efficacy of EUS-B-FNA in suspected lung cancer patients with poor respiratory or general conditions. Methods Patients with suspected lung cancer with respiratory failure, Eastern Cooperative Oncology Group performance status of 2 or higher, or severe respiratory symptoms, were enrolled. The primary endpoints were the diagnostic yield of lung cancer and its safety, and the secondary endpoints were the success rate of molecular and programmed death ligand 1 (PD-L1) analyses, and the 6-month survival rate in patients with lung cancer. Results We enrolled 30 patients, of which 29 were included in the analysis. Among them, 26 were eventually diagnosed with lung cancer. The diagnostic yield for lung cancer was 100% (26/26). There were no adverse events associated with EUS-B-FNA requiring procedure discontinuation. The success rates of molecular analysis for EGFR, ALK, ROS-1, and BRAF were 100% (14/14), 100% (11/11), 100% (9/9), and 75% (6/8), respectively. The success rate of the PD-L1 analysis was 100% (15/15). The 6-month survival rate in patients with lung cancer was 53.8% (95% confidence interval [CI]: 33.4–76.4), and the median overall survival (OS) was 196 days (95% CI: 142–446). Conclusions EUS-B-FNA is a safe and effective diagnostic method, even in patients with suspected lung cancer with poor respiratory or general conditions. Trial registration This clinical trial was registered at https://www.umin.ac.jp/ctr/index.htm (UMIN000041235, approved on 28/07/2020).

The influence of aneurysm size on the outcomes of endovascular management (EM) for aneurysmal subarachnoid hemorrhages (aSAH) is poorly understood. To evaluate the outcomes of EM for ruptured large cerebral aneurysms, we retrospectively analyzed the medical records of patients with aSAH that were treated with coiling between 2013 and 2020 and compared the differences in outcomes depending on aneurysm size. A total of 469 patients with aSAH were included; 73 patients had aneurysms measuring 10 mm in diameter (group L), and 396 had aneurysms measuring

The trichothecene biosynthesis in Fusarium begins with the cyclization of farnesyl pyrophosphate to trichodiene, followed by subsequent oxygenation to isotrichotriol. This initial bicyclic intermediate is further cyclized to isotrichodermol (ITDmol), a tricyclic precursor with a toxic trichothecene skeleton. Although the first cyclization and subsequent oxygenation are catalyzed by enzymes encoded by Tri5 and Tri4, the second cyclization occurs non-enzymatically. Following ITDmol formation, the enzymes encoded by Tri101, Tri11, Tri3, and Tri1 catalyze 3-O-acetylation, 15-hydroxylation, 15-O-acetylation, and A-ring oxygenation, respectively. In this study, we extensively analyzed the metabolites of the corresponding pathway-blocked mutants of Fusarium graminearum. The disruption of these Tri genes, except Tri3, led to the accumulation of tricyclic trichothecenes as the main products: ITDmol due to Tri101 disruption; a mixture of isotrichodermin (ITD), 7-hydroxyisotrichodermin (7-HIT), and 8-hydroxyisotrichodermin (8-HIT) due to Tri11 disruption; and a mixture of calonectrin and 3-deacetylcalonectrin due to Tri1 disruption. However, the ΔFgtri3 mutant accumulated substantial amounts of bicyclic metabolites, isotrichotriol and trichotriol, in addition to tricyclic 15-deacetylcalonectrin (15-deCAL). The ΔFgtri5ΔFgtri3 double gene disruptant transformed ITD into 7-HIT, 8-HIT, and 15-deCAL. The deletion of FgTri3 and overexpression of Tri6 and Tri10 trichothecene regulatory genes did not result in the accumulation of 15-deCAL in the transgenic strain. Thus, the absence of Tri3p and/or the presence of a small amount of 15-deCAL adversely affected the non-enzymatic second cyclization and C-15 hydroxylation steps.

Middle meningeal artery embolization (MMAE) for chronic subdural hematoma (CSDH) is a novel, minimally invasive treatment. The indications and treatment practices for MMAE are variable and remain controversial. This study aimed to evaluate a strategy involving sequential MMAE after burr hole surgery for treating recurrent CSDH. We performed a retrospective analysis of data from consecutive patients who had undergone MMAE using liquid embolic agents within approximately 2 weeks after burr hole surgery for recurrent CSDH from September 2020 to March 2022. We analyzed patient characteristics, procedural details, CSDH recurrence after MMAE, surgical rescue, and complications. Six of the nine patients who underwent MMAE for CSDH recurrence were male, and the median age was 85 (range, 70-94) years. Five of the nine patients were being administered antithrombotic agents. The median duration between the burr hole surgery and MMAE procedure was 10 (range, 3-25) days. Anterior and posterior convexity branches were targeted for embolization using low-concentration N-butyl cyanoacrylate (NBCA), and the abnormal vascular networks with a cotton wool appearance disappeared after embolization in all cases. The NBCA distribution was observed by high-resolution computed tomography during the procedure; in three of nine cases, the NBCA penetrated not only the MMA but also the inner membrane. No recurrence, surgical rescue, or complications were observed in any patient during the median follow-up period of 3 months. As a minimally invasive treatment for recurrent CSDH, sequential MMAE after burr hole surgery may be a safe and effective option for preventing recurrence.

Abstract The COVID‐19 pandemic is an outstanding global threat for both human health and well‐being. Under the pandemic, green spaces are known to mitigate the physical/mental stress of urban people. However, it remains unclarified how blue spaces such as coastal and river areas play a role in healing urban people's health and well‐being during the pandemic. Here, conducting an online‐based survey in Japanese megacities, with 5756 responses received from residents of Tokyo, Yokohama, Osaka and Kobe, we examined the effects of personal characteristics of city residents on their visitation frequencies to blue spaces during and after the emergency periods, and compared visitation purposes and motivation between the coastal and river areas. Cumulative linear modelling revealed that people with more nature experiences in childhood and higher satisfaction of neighbourhood coasts and rivers visited urban blue spaces more frequently. In addition, those who lived with pre‐school and primary school children also visited urban blue spaces more frequently than those without, likely for letting them play in blue spaces. These people primarily visited them to decrease their stress and to maintain their health by contacting with nature while keeping social distance to avoid being infected. Moreover, the visitation purpose and motivation partly differed between the coastal and river areas, which could be explained by the accessibility to and perception of blue spaces for urban people. The present study implies that, as well as green spaces, blue spaces provided places that people in urban areas could use to mitigate their stress and disorder during the pandemic. Our findings underpin the necessity of preserving both of them in urban planning for further benefits relating to health and well‐being. Read the free Plain Language Summary for this article on the Journal blog.

This study focused on rivers as an urban blue space and investigated how urban residents perceive the biodiversity of rivers around their homes to understand whether people’s evaluation of biodiversity changes depended on the extent of their nature experiences. Quantitative data measured by the environmental DNA method were used as an indicator of biodiversity, while urban residents' perceptions of the river and their experiences of nature were ascertained by conducting a social survey. A regression analysis of 312 responses of people living in the catchment areas around 20 rivers showed that for participants with more childhood nature experiences, their satisfaction with their neighborhood waterfront areas tended to increase as river biodiversity increased. However, for those who have had fewer childhood experiences with nature, an increase in biodiversity resulted in lower satisfaction with waterfront areas. These results indicate that modern urban residents with little experience with nature tend to prefer concrete paved rivers for their recreational value and walkability rather than rivers with high biodiversity.

Abstract Background This cross-sectional study performed to clarify the relationship between periodontal disease and non-communicable diseases (NCDs), such as obesity, diabetes mellitus, impaired glucose tolerance (IGT), chronic obstructive pulmonary disease (COPD), and atherosclerotic cardiovascular disease (ASCVD) by introducing dental examinations into the annual health examinations conducted by Japanese companies, and to highlights the importance of a medical system that connects dental and medical professionals. Methods A total of 1.022 Hitachi Ltd. employees were enrolled in this cross-sectional study. We examined correlations and odds ratios (ORs) between the dental and overall health of employees using stratification and multiple logistic regression analyses based on the periodontal health indicators, general health indicators, and occlusal force. Results The adjusted OR of PPD for obesity (OR, 1.42; 95% confidence interval [CI], 1.09–1.84; p = 0.009), IGT (OR, 1.48; 95% CI, 1.00–2.20; p = 0.049), and COPD (OR, 1.38; 95% CI, 1.02–1.88; p = 0.038) significantly differed. The adjusted OR of body mass index (OR, 1.28; 95% CI 1.15–1.42; p

Abstract Background Lacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis. Case presentation The patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9th hospital day. Severe SND developed on the 10th hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11th hospital day, and the patient died from septic shock on the 15th hospital day. Conclusions This case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.

Abstract Aims Prognostic impacts of serum uric acid (UA) levels in patients with chronic heart failure (CHF) remain inconclusive, especially for the whole range of serum UA levels. Methods and results In the Chronic Heart Failure Registry and Analysis in the Tohoku District‐2 (CHART‐2) study, we enrolled 4652 consecutive patients with CHF and classified them into four groups based on baseline serum UA levels by the Classification and Regression Tree: G1 (9.2 mg/dL, N = 251). Mean age was 71 ± 12, 69 ± 12, 68 ± 13, and 69 ± 15 years in G1, G2, G3, and G4, respectively (P

Combinatorial clustering based on the Ising model is drawing attention as a high-quality clustering method. However, conventional Ising-based clustering methods using the Euclidean distance cannot handle irregular data. To overcome this problem, this paper proposes an Ising-based kernel clustering method. The kernel clustering method is designed based on two critical ideas. One is to perform clustering of irregular data by mapping the data onto a high-dimensional feature space by using a kernel trick. The other is the utilization of matrix–matrix calculations in the numerical libraries to accelerate preprocess for annealing. While the conventional Ising-based clustering is not designed to accept the transformed data by the kernel trick, this paper extends the availability of Ising-based clustering to process a distance matrix defined in high-dimensional data space. The proposed method can handle the Gram matrix determined by the kernel method as a high-dimensional distance matrix to handle irregular data. By comparing the proposed Ising-based kernel clustering method with the conventional Euclidean distance-based combinatorial clustering, it is clarified that the quality of the clustering results of the proposed method for irregular data is significantly better than that of the conventional method. Furthermore, the preprocess for annealing by the proposed method using numerical libraries is by a factor of up to 12.4 million × from the conventional naive python’s implementation. Comparisons between Ising-based kernel clustering and kernel K-means reveal that the proposed method has the potential to obtain higher-quality clustering results than the kernel K-means as a representative of the state-of-the-art kernel clustering methods.

Bangladesh, the poster child of human-induced climate change, bears the brunt of the consequences of extreme climatic events such as floods, droughts, cyclones, salinity, and sea-level rise (SLR). In addition, the frequency and intensity of these extreme climatic events are shooting upward. They jeopardize households’ cereal food consumption in areas where the outbreak and landfall of these events are moderate and severe. Using Bangladesh—the most climate-vulnerable country globally—as a case study, this study investigates whether extreme climatic events have a heterogeneous impact on each region's agriculture through households’ food consumption. Using three rounds of nationally representative longitudinal datasets and employing a difference-in-differences (DiD) approach, results confirm that cyclone and saline-prone areas of the country are more vulnerable, followed by drought and flood-affected areas of cereal food consumption. In the long run (2011–19), Model 1 (per household cereal food consumption) was significant at the 1% and 10% levels, respectively, in the cyclone and drought-prone areas, but for flood-prone areas, it was insignificant. Moreover, analysis considering base year whole sample as control also underpinned that climate variability and their correlates negatively impact households’ basic food consumption. In the upshots findings, therefore, the study recommends intensifying agricultural research through robust budget allocation, launching crop insurance scheme and development of variety and technology sustaining in the saline, drought, and flood-prone areas along with high promotion for the adoption of the cultivars as well as strengthening of flood forecasting and early warning system.

To study the toxicity of 3-hydroxybenzo[c]phenanthrene (3-OHBcP), a metabolite of benzo[c]phenanthrene (BcP), first we compared it with its parent compound, BcP, using an in ovo-nanoinjection method in Japanese medaka. Second, we examined the influence of 3-OHBcP on bone metabolism using goldfish. Third, the detailed mechanism of 3-OHBcP on bone metabolism was investigated using zebrafish and goldfish. The LC50s of BcP and 3-OHBcP in Japanese medaka were 5.7 nM and 0.003 nM, respectively, indicating that the metabolite was more than 1900 times as toxic as the parent compound. In addition, nanoinjected 3-OHBcP (0.001 nM) induced skeletal abnormalities. Therefore, fish scales with both osteoblasts and osteoclasts on the calcified bone matrix were examined to investigate the mechanisms of 3-OHBcP toxicity on bone metabolism. We found that scale regeneration in the BcP-injected goldfish was significantly inhibited as compared with that in control goldfish. Furthermore, 3-OHBcP was detected in the bile of BcP-injected goldfish, indicating that 3-OHBcP metabolized from BcP inhibited scale regeneration. Subsequently, the toxicity of BcP and 3-OHBcP to osteoblasts was examined using an in vitro assay with regenerating scales. The osteoblastic activity in the 3-OHBcP (10-10 to 10-7 M)-treated scales was significantly suppressed, while BcP (10-11 to 10-7 M)-treated scales did not affect osteoblastic activity. Osteoclastic activity was unchanged by either BcP or 3-OHBcP treatment at each concentration (10-11 to 10-7 M). The detailed toxicity of 3-OHBcP (10-9 M) in osteoblasts was then examined using gene expression analysis on a global scale with fish scales. Eight genes, including APAF1, CHEK2, and FOS, which are associated with apoptosis, were identified from the upregulated genes. This indicated that 3-OHBcP treatment induced apoptosis in fish scales. In situ detection of cell death by TUNEL methods was supported by gene expression analysis. This study is the first to demonstrate that 3-OHBcP, a metabolite of BcP, has greater toxicity than the parent compound, BcP.

This study uses empirical methods to explore the relationship between subway system development and air quality in the Yangtze River Delta. We propose a new variable to measure subway development, ‘subway station density value,’ which can more accurately describe subway development than the traditional ‘line opening’ variable. It eliminates the effects of differences in subway line length, layout, and size of the local subway system. Using this variable, we find that subway development has a significant positive impact on air quality improvement; that is, an increase in the density of subway stations is significantly associated with improved air quality. This finding provides a scientific basis for the relevant authorities to formulate the development and layout of public transport facilities. It strongly responds to previous debates on the relationship between subways and air quality. In addition, we find that urban population size, economic development level, and subway system size play moderating roles in the relationship between subways and air quality. Increasing the availability of subways can significantly improve the air quality in cities with high population sizes and economic development levels. However, as the size of a subway system increases, its effect on air quality improvement may weaken, suggesting that the development of subway systems should not be unthinkingly expanded either. Although our study has valuable findings, we must discuss several limitations further. These include restrictions in the selection of the study population, data availability, and potentially oversimplified criteria for considering the impact of urban differences. Overall, this study not only provides new theoretical and empirical perspectives for understanding and explaining how subway development affects air quality but also indicates the direction for further exploration in future studies.

We hypothesized that gait treatment with a wearable cyborg Hybrid Assistive Limb (HAL) would improve the walking ability of patients with hemiparesis after stroke. This study aims to evaluate the efficacy and safety of gait treatment using HAL versus conventional gait training (CGT) in hemiplegic patients with acute stroke and establish a protocol for doctor-initiated clinical trials for acute stroke. We will enroll patients with acute stroke at the University of Tsukuba Hospital. This study is a single-center, randomized, parallel-group, controlled trial (HAL group, n = 20; control group, n = 20) that will include three phases: (1) pre-observation phase (patient enrollment, baseline assessment, and randomization); (2) treatment phase (nine sessions, twice or thrice per week over 3−4 weeks; the HAL and control groups will perform gait treatment using HAL or CGT, respectively, and finally (3) post-treatment evaluation phase. The Functional Ambulation Category score will be the primary outcome measure, and the following secondary outcome measures will be assessed: Mini-Mental State Examination, Brunnstrom recovery stage of lower limbs, Fugl–Meyer assessment of lower limbs, 6-min walking distance, comfortable gait speed, step length, cadence, Barthel Index, Functional Independence Measure, gait posture, motion analysis (muscle activity), amount of activity (evaluated using an activity meter), stroke-specific QOL, and modified Rankin Scale score. The baseline assessment, post-treatment evaluation, and follow-up assessment will evaluate the overall outcome measures; for other evaluations, physical function evaluation centered on walking will be performed exclusively, excluding ADL and QOL scores. This study is a randomized controlled trial that aims to clarify the efficacy and safety of gait treatment using HAL compared with CGT in hemiplegic patients with acute stroke. In addition, we aim to establish a protocol for doctor-initiated clinical trials for acute stroke based on the study results. If our results demonstrate the effectiveness of the proposed treatment regarding outcomes of patients with hemiplegic acute stroke, this study will promote the treatment of these patients using the HAL system as an effective tool in future stroke rehabilitation programs. The study protocol was registered with the Japan Registry of Clinical Trials on October 14, 2020 (jRCTs032200151).

Background Anti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We determined whether changes in 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET parameters before and soon after treatment initiation predicted the therapeutic effect of anti-PD-1 antibody.Methods Twenty-six patients with advanced NSCLC treated with anti-PD-1 antibody were enrolled prospectively and underwent 18F-FLT PET before and at 2 and 6 weeks after treatment initiation. Changes in maximal standardized uptake value (ΔSUVmax), proliferative tumor volume (ΔPTV) and total lesion proliferation (ΔTLP) of the lesions were calculated and evaluated for their associations with the clinical response to therapy.Results The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLP at 2 weeks, and decreased SUVmax, PTV, and TLP at 6 weeks, compared with those with PD, while three of eight (37.5%) patients who responded had increased TLP from baseline at 2 weeks (ie, pseudoprogression). Among the parameters that changed between baseline and 2 weeks, ΔPTV0-2 and ΔTLP0-2 had the highest accuracy (76.0%) to predict PD. Among the parameters that changed between baseline and 6 weeks, ΔSUVmax0-6, ΔPTV0-6 and ΔTLP0-6 had the highest accuracy (90.9%) to predict PD. ΔTLP0-2 (≥60%, HR 3.41, 95% CI 1.34–8.65, p=0.010) and ΔTLP0-6 (≥50%, HR 31.4, 95% CI 3.55 to 276.7, p=0.0019) were indicators of shorter progression-free survival.Conclusions Changes in 18F-FLT PET parameters may have value as an early predictive biomarker for the response to anti-PD-1 therapy in patients with NSCLC. However, it should be noted that pseudoprogression was observed in 18F-FLT PET imaging at 2 weeks after treatment initiation.Trial registration number jRCTs051180147.

Paraneoplastic neurological syndrome (PNS) is associated with malignancies, such as small-cell lung cancer. However, patients with non-small cell lung cancer (NSCLC) rarely develop PNS. We herein report a 72-year-old man with NSCLC who developed disturbance of consciousness on the day of initiation of treatment with an immune checkpoint inhibitor. Blood test results revealed anti-amphiphysin (AMPH) antibody positively, leading to the diagnosis of PNS. The disturbance of consciousness was improved with intravenous administration of steroid and immunoglobulin. To our knowledge, this is the first report of anti-AMPH antibody-positive PNS in a patient with NSCLC.

We report a case of superficial siderosis (SS) of the central nervous system that developed approximately 8 years after the treatment of cerebral arteriovenous malformation (AVM). A 17-year-old boy was diagnosed with cerebral AVM in the right frontal lobe, which was treated with embolization and radiation therapy. Radiation-induced encephalopathy occurred 5 years later, and the lesion was resected. Although the patient could walk with a cane following the surgery and rehabilitation, he exhibited complete paresis of the left upper extremity. In the course of the next 9 years, he showed cognitive function decline, paresis of the lower right extremity, and the inability to walk. He also exhibited dysarthria and paresis of the right arm. Respiratory failure developed at age 39 years, necessitating mechanical ventilation. Cerebral angiography revealed no recurrence of cerebral AVM; however, brain and spinal magnetic resonance imaging revealed broad hemosiderin deposition, which is characteristic of SS, and the presence of a postoperative cyst that was suspected to be the bleeding source. While eliminating the source of the bleeding is considered the best line of treatment for SS, this was not pursued due to the patient's irreversible neurological condition. Thus, clinicians should consider SS as a differential diagnosis for patients that exhibit gradual and progressive neurological defects several years after successful AVM treatment. Keywords: Superficial siderosis, Radiation-induced encephalopathy, Arteriovenous malformation

Background: Since most of the randomized clinical trials for heart failure (HF) were designed to exclude elderly patients, limited data are available on their clinical characteristics, prognosis, and prognostic factors. Methods: We compared clinical characteristics, prognosis, and prognostic factors among Stage C/D HF patients in our CHART-2 Study (N = 4876, mean 69 years, women 32%, 6.3-year follow-up) by age (G1, ≤64 years, N = 1521; G2, 65–74 years, N = 1510; and G3, ≥75 years, N = 1845). Results: From G1 to G3, the prevalence of women, left ventricular ejection fraction (LVEF) and plasma levels of B-type natriuretic peptide (BNP) increased (all P

We hypothesized that a single-leg version of the Hybrid Assistive Limb (HAL) system could improve the gait and physical function of patients with hemiparesis following a stroke. In this pilot study, we therefore compared the efficacy of HAL-based gait training with that of conventional gait training (CGT) in patients with acute stroke. Patients admitted to the participating university hospital were assigned to the HAL group, whereas those admitted to outside teaching hospitals under the same rehabilitation program who did not use the HAL were assigned to the control group. Over 3 weeks, all participants completed nine 20 min sessions of gait training, using either HAL (i.e., the single-leg version of HAL on the paretic side) or conventional methods (i.e., walking aids and gait orthoses). Outcome measures were evaluated before and after the nine training sessions. The Functional Ambulation Category (FAC) was the primary outcome measure, but the following secondary outcome measures were also assessed: National Institutes of Health Stroke Scale, Fugl–Meyer Assessment (Lower Extremity), comfortable walking speed, step length, cadence, 6-min walk distance, Barthel Index, and Functional Independence Measure. In total, 22 post-stroke participants completed the clinical trial: 12 in the HAL group and 10 in the CGT group. No serious adverse events occurred in either group. The HAL group showed significant improvement in FAC after nine sessions when compared with the CGT group (P = 0.014). However, secondary outcomes did not differ significantly between the groups. Our results demonstrate that HAL-based gait therapy may improve independent walking in patients with acute stroke hemiplegia who are dependent on ambulatory assistance. A larger-scale randomized controlled trial is needed to clarify the effectiveness of single-leg HAL therapy.Clinical Trial Registration: UMIN Clinical Trials Registry, identifier UMIN000022410.

This paper addresses the simultaneous design of observer-based robust scaled-H8 controllers and scaling matrices for discrete-time linear time-invariant polytopic systems. Based on the so-called dilated linear matrix inequality approach, we propose a design method for our problem with a structural constraint for the decision matrix which is introduced in “dilation” procedure. The structural constraint inevitably introduces conservatism; however, numerical examples illustrate the effectiveness of the simultaneous design of controller matrices, i.e. observer gain, state-feedback gain, the state transition matrix of the observer, and the input or the output matrix of the observer, as well as the scaling matrix.

The safety of nanomaterials is still being debated and the risk should be assessed using the latest available information. As for poorly soluble low toxic (PSLT) nanomaterials, the US National Institute for Occupational Safety and Health estimated the occupational exposure limit (OEL) for titanium dioxide (TiO2) based on a particle surface area (SA) metric. The Organisation for Economic Co-operation and Development (OECD) suggested a tiered exposure assessment approach. This article proposes a risk assessment framework for self-management of PSLT particles. Lung burden (described in SA units), which had positive correlation with low observed adverse effect levels for PSLT particles, is chosen as the dose metric. In-house OEL is determined for individual workplaces. For materials with limited data, we suggest evaluating in-house OEL by utilizing the no observed adverse effect level (NOAEL) for TiO2, as a representative PSLT nanomaterial. As for the exposure assessment, workplace concentration is first measured with simple equipment (ex. optical particle counter, OPC), and respirator performance is taken into account if it is unavoidable as a last resort. This framework enables efficient risk assessment for PSLT particles by assuming worst cases for each step, and considering the particle characteristics and operational conditions in each workplace.

BackgroundCombined renal dysfunction worsens the subsequent prognosis in patients after acute myocardial infarction (AMI). Therefore, establishing a therapeutic modality to maintain or improve renal function in AMI patients is necessary. This study aimed to elucidate the association between physical activity level and change in renal function in such patients.DesignProspective and observational study.MethodsWe enrolled 41 patients (35 men; average age, 67.5 ± 12.6 years) after AMI onset. Blood biochemistry, urinalysis, and physical function tests were conducted at discharge and 3 months after discharge. Renal function was evaluated based on cystatin C based-estimated glomerular filtration rate (eGFRcys). The number of steps was recorded for 3 months post-discharge. Generalized estimating equations (GEE) was used to test the association between physical activity level and within-patient changes in eGFRcys.ResultsPatients were stratified into low (n = 21; number of steps, 2335 ± 1219 steps/day) and high groups (n = 20; number of steps, 7102 ± 2365 steps/day). eGFRcys significantly increased from baseline to after 3 months in the high group (76.5 ± 13.8 to 83.2 ± 16.0 mL/min/1.73 m2, q = 0.004), whereas no significant change was observed in the low group (65.1 ± 15.9 to 62.2 ± 20.2 mL/min/1.73 m2, q = 0.125). Result of GEE adjusted for potential confounding variables showed a significant positive association between physical activity level and within-patient changes in eGFRcys (p = 0.003). Changes in eGFRcys was -2.9 mL/min/1.73 m2 among low group versus +6.7 mL/min/1.73 m2 among high group.ConclusionsPhysical activity level was positively associated with changes in renal function, demonstrating that high physical activity may suppress renal function decline in patients after AMI.

Quad-Tilt-Wing (QTW) Unmanned Aerial Vehicle (UAV) is one of the promising types of UAVs because of its high-speed cruise performance similar to fixed-wing aircraft and VTOL (Vertical TakeOff and Landing) ability like helicopters. The control performance of our previously designed Control Augmentation System (CAS) for the aircraft was not satisfactory due to the oscillatory motions in flight tests. This paper thus presents an H∞ control-based robust CAS design for QTW-UAV via multiple-model approach with Particle Swarm Optimization (PSO) to suppress the oscillatory motions. Although the adoption of the multiple-model approach to obtain robust CAS gains is the same as in our previous design, our new method has two unique features in contrast to the previously used method, that is, the design requirement for CAS gains is given in the frequency domain to shape the frequency responses from attitude command to attitude error and PSO is used to reduce the numerical complexity coming from a brute-force method, i.e., the gridding method. The overall control performance of the designed CAS gains is examined by human-in-the-loop nonlinear flight simulations. As an extension of the proposed method, we consider the situation in which uncertainty models with different probabilistic densities should be incorporated into the nominal model and show that the nominal performance can be improved at the expense of slight performance degradation for the models with small probabilistic density.

Adhesion to intestinal mucus is the first event in the process by which intestinal microbes colonize the intestine. It plays a critical role in the initiation of interactions between gut microbes and host animals. Despite the importance, the adhesion properties of probiotics are generally characterized using porcine mucin; adhesion to human mucus has been poorly characterized. In the present study, human intestinal mucus samples were isolated from 114 fecal samples collected from healthy infants and adults. In initial screening, four out of the 13 beneficial microbes tested, including the type strain of Bifidobacterium bifidum, B. bifidum TMC3115, Lacticaseibacillus rhamnosus GG, and Bifidobacterium animalis subsp. lactis Bb12, showed strong adhesion abilities to human mucus. The type strain of B. bifidum and TMC3115 adhered more strongly to neonatal and infant mucus than to adult mucus, while L. rhamnosus GG and B. lactis Bb12 adhered more strongly to adult mucus than to infant mucus. Similar results were obtained for ten additional strains of B. bifidum. In conclusion, age/generation-related differences were observed in the adhesion properties of B. bifidum and other strains. A deeper symbiotic relationship may exist between infants, particularly neonates, and B. bifidum based on its enhanced adhesion to neonatal intestinal mucus.

BackgroundThe beneficial prognostic impact of statins has been established in patients with ischemic heart disease but not in those with heart failure (HF). In addition, it is still unclear whether patients benefit from statins regardless of low‐density lipoprotein cholesterol levels. Methods and ResultsWe examined 2444 consecutive stage C or D HF patients with ischemic heart disease registered in CHART‐2 (Chronic Heart Failure Registry and Analysis in the Tohoku District 2), a multicenter, prospective, observational cohort study in Japan. Patients were divided into 3 groups according to the Japanese standard doses of statins and statin‐intensity categories defined by the 2013 American College of Cardiology and American Heart Association guidelines: higher (moderate‐high)‐intensity (n=868), lower (low)‐intensity (n=526), and no statin (n=1050). The median follow‐up period was 6.4 years (13929 person‐years). Analysis with the inverse probability of treatment weighted using a propensity score for multiple treatment revealed that both the higher‐intesity group (hazard ratio [HR]: 0.68; P

Recent studies have shown that rebamipide, which suppresses reactive oxygen species, prevents chemoradiotherapy-induced oral mucositis in patients with head and neck cancers. However, anticancer action of radiotherapy and chemotherapy is believed to be partially associated with generation of reactive oxygen species. The aim of this study was to determine whether rebamipide interferes with the antitumor action of radiotherapy and chemotherapy. The effect of rebamipide on tumor cell growth was investigated using a human oral squamous carcinoma cell line, HSC-2, in vitro and in vivo. Rebamipide showed no significant effect on cell or tumor growth in HSC-2 tumor-bearing nude mice. Influences of rebamipide on the antitumor action of radiotherapy and of chemotherapy with cisplatin or docetaxel were investigated using the same animal model. In radiotherapy, the tumor was treated with 2.5 Gy of X-rays for 5 days, and rebamipide (300 mg/kg p.o.) was administered during irradiation periods. In chemotherapy, tumor-bearing mice were treated once with cisplatin (8 mg/kg, i.v.) or docetaxel (15 mg/kg i.v.) and rebamipide (300 mg/kg p.o.) was administered for 5 days following the antitumor drug treatment. Rebamipide did not interfere with the antitumor action of radiotherapy and chemotherapy.

In patients with left ventricular (LV) dysfunction, diuretics can reduce blood pressure and lead to electrolyte abnormalities. The aim of this study was to compare the effects of tolvaptan (T group) and carperitide (C group) in these patients. Sixty-one consecutive patients admitted to the Iwate Prefectural Kuji Hospital or the Emergency Center of the Iwate Medical University between July 2011 and April 2015 were included in this study. These patients had acute heart failure (HF) and were initially treated with furosemide. Patients were excluded from the study if they received combined carperitide and tolvaptan, if they received tolvaptan or cardiotonic drugs prior to the study period, if their LV ejection fraction was ≥40%, and if they had renal dysfunction (serum creatinine > 2.0 mg/dL). There were no differences in the change in serum electrolytes in both groups, and none of the patients in the T group received supplementary dobutamine therapy. Oxygen administration was stopped successfully after a significantly shorter treatment period in the T group. These findings suggest that patients treated with tolvaptan did not require dobutamine as frequently as those treated with carperitide and indicated that tolvaptan may improve respiratory function more rapidly in patients with LV dysfunction.

Objective. This study examined the hypothesis that correlations exist between the carbon monoxide exposure time and the carboxyhemoglobin concentration at the site of carbon monoxide poisoning, using a pulse carbon monoxide oximeter in rural areas or the carboxyhemoglobin concentration measured at a given medical institution. Background. In previous studies, no definitive relationships between the arterial blood carboxyhemoglobin level and the severity of carbon monoxide poisoning have been observed. Method. The subjects included patients treated for acute carbon monoxide poisoning in whom a medical emergency team was able to measure the carboxyhemoglobin level at the site of poisoning. We examined the relationship between the carboxyhemoglobin level at the site of poisoning and carbon monoxide exposure time and the relationships between the arterial blood carboxyhemoglobin level and carbon monoxide exposure time. Results. A total of 10 patients met the above criteria. The carboxyhemoglobin levels at the site of poisoning were significantly and positively correlated with the exposure time (rs = 0.710, p=0.021), but the arterial blood carboxyhemoglobin levels were not correlated with the exposure time. Conclusion. In rural areas, the carboxyhemoglobin level measured at the site of carbon monoxide poisoning correlated with the exposure time.

We report a case of multiple benign metastasizing leiomyoma (BML) lung nodules showing faint or non-avid uptake of F-18 fluorodeoxyglucose (FDG) (respective 1-hour early and 2-hour delayed maximum standardized uptake values; 1.3 or less and 1.2 or less) in a 50-year-old woman with a history of hysterectomy for uterine leiomyoma at the age of 38 years. When multiple lung nodules show faint or non-avid FDG uptake in a patient with a history of hysterectomy for uterine leiomyoma, BML should be included in the differential diagnosi.

We previously reported that maternal protein restriction (LP) during pregnancy increases salt sensitivity in offspring using the Stroke-Prone Spontaneously Hypertensive Rat (SHRSP). In the present study, we focus on DNA methylation profiles of prostaglandin E receptor 1 gene (ptger1), which is known to be associated with hypertension. We evaluated the ptger1 DNA methylation status via bisulfite sequencing, and analyzed the expression of ptger1-related genes. The results of these analyses showed that, compared to controls, the LP-S offspring exhibited both marked ptger1 hypermethylation, and significantly increased ptger1 expression. Moreover, they also exhibited significantly decreased expression of the downstream gene epithelial Na+ channel alpha (enacα). Interestingly, LP offspring that were provided with a standard water drinking supply (W) also exhibited increased ptger1 methylation and expression. Together, these results suggest that maternal protein restriction during pregnancy modulates the renal ptger1 DNA methylation state in SHRSP offspring, and thereby likely mediates ptger1 and enacα gene expression to induce salt sensitivity.

We previously reported that a soluble CD14-subtype (sCD14-ST) immunochromatographic test (ICT) for plasma is more convenient than chemiluminescent enzyme immunoassay (CLEIA), but plasma separation makes bedside measurements difficult. We developed a new sCD14-ST ICT for whole blood and investigated whether quantitative determinations of sCD14-ST by ICT were useful for diagnosing sepsis and severe sepsis/septic shock. We studied 20 patients who fulfilled two or more systemic inflammatory response syndrome (SIRS) criteria and 32 patients who had been diagnosed with sepsis or severe sepsis/septic shock. Whole blood was collected on day 0 (on admission) and day 7, and the sCD14-ST concentration was quantitatively measured by CLEIA and ICT for whole blood. The patients' Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores were also calculated. The cut-off values obtained by the quantitative measurements made by ICT were 464.5 pg/mL for sepsis and 762.7 pg/mL for severe sepsis/septic shock (P < 0.0001). A Bland-Altman plot showed that no fixed bias or proportional bias was detected between CLEIA and quantitative ICT for whole blood. sCD14-ST concentrations were significantly correlated with APACHE II, SOFA, and MEDS scores (P < 0.0001). These results suggest that the new sCD14-ST ICT for whole blood may be a useful tool for the convenient, rapid bedside diagnosis and treatment of sepsis.

Depth perception from motion parallax has been investigated with right-and-left head movement. From ecological point of view, humans move forward more frequently than sideways. The aim of this study was to determine the influence of the head movement direction on depth perception from motion parallax. We investigated depth perception at and above threshold level with lateral head movement and to-and-fro movement. Stimuli were vertical half cylinders, which was concave or convex, depicted with random dots that move synchronously with head. The viewing distance was 78.5 cm on average. The size of each display was 6.6 × 6.6 deg. The dot density in the entire display was always maintained constant for prevention of depth impression from difference in dot density. Four subjects participated the experiments. Mean threshold for lateral and to-and-fro motion were about 0.1 cm and 5 cm respectively. Mean gains of apparent depth for lateral and to-and-fro motion were about 1 and 0.2, respectively.

The visual phenomenon that perceived depth sign is opposite to depth sign geometrically predicted from binocular disparity or motion parallax is known as depth reversal (Gillam, 1967; Hayashibe, 1991). Combination of binocular disparity and motion parallax generally improve depth perception (Nawrot & Blake, 1991). In the current study, we investigated if the combined display contributes to the fixing of depth reversal. In a dark room, a surface slanted about a vertical axis was displayed for 800 ms by binocular cue only, by motion cue only, or by binocular and motion cues. Six subjects judged the apparent slant. Overall, mean frequencies of reports of reverse slant were 78.2%, 36.8%, and 78.6% for binocular cue only, motion cue only, and binocular and motion cues, respectively. Namely, combination of binocular disparity and motion parallax does not contribute to the fixing of depth reversal.

A surface lying in a frontal plane appears slanted about a vertical axis when the image in one eye is horizontally magnified relative to the image in the other eye. This is predicted from the geometry of the situation. The same surface appears to slant in the opposite direction when the image in the first eye is vertically magnified relative to the image in the other eye (induced effect). One explanation of the induced effect is that the retinal image is isotropically scaled to the same height and the horizontal magnification disparity as a by-product elicits the slant impression. In the current study, scaling of retinal image induced by the stereogram with vertical magnification disparity is investigated. Two horizontal lines were superimposed on the stereogram to measure the scaling. One line presented to one eye was parallel to the other line presented to the other eye, to avoid problems of rivalry or fusion. Three subjects responded apparent lengths of the lines. The result showed that the line superimposed on the vertically magnified image appeared longer than the other line. This supports that scaling of retinal image induced by vertical magnification exists.

Fisher and Ciuffreda (1988) and Mon-Williams and Tresilian (1999) reported that, without vergence cue, diopter change in accommodation induced change in apparent distance. Meanwhile, there is conflicting evidence about the relative roles of accommodation and vergence in distance perception (Richards & Miller, 1969; von Holst, 1973). In the current study, we investigated interaction between accommodation and vergence on distance perception. The perceived distance from integration of vergence evoked by a fixation target and accommodation by a pair of concave or convex lenses in front of eyes is measured with a mirror stereoscope. The stimulus was a white square with a black cross-shaped fixation on a black background. In dark surroundings, subjects were asked to commit the apparent distance of the target to memory, and then without the lenses, re-create the distance by changing distance of another fixation target. The apparent size of the target through lenses were equivalent to the size without lenses. The results showed that not only vergence but accommodation affect the apparent distance, and they were summed linearly.